Discovery of MDV6058 (PF-06952229), a selective and potent TGFßR1 inhibitor: Design, synthesis and optimization.

Compound 1 is a potent TGF-ß receptor type-1 (TGFßR1 or ALK5) inhibitor but is metabolically unstable. A solvent-exposed part of this molecule was used to analogue and modulate cell activity, liver microsome stability and mouse pharmacokinetics. The evolution of SAR that led to the selection of 2 (MDV6058 / PF-06952229) as a preclinical lead compound is described.

Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors.

Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice.

Discovery of pyrazolopyrimidine derivatives as novel inhibitors of ataxia telangiectasia and rad3 related protein (ATR).

The ATR pathway is a critical mediator of the replication stress response in cells. In aberrantly proliferating cancer cells, this pathway can help maintain sufficient genomic integrity for cancer cell progression. Herein we describe the discovery of 19, a pyrazolopyrimidine-containing inhibitor of ATR via a strategic repurposing of compounds targeting PI3K.

Targeting prostate cancer with compounds possessing dual activity as androgen receptor antagonists and HDAC6 inhibitors.

While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20-40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios. With dual-acting AR-HDAC6 inhibitors it should be possible to target patients who don't respond to enzalutamide. Herein, we describe the design, synthesis and biological evaluation of dual-acting compounds which target AR and are also specific towards HDAC6. Our efforts led to compound 10 which was found to have potent dual activity (HDAC6 IC50=0.0356µM and AR binding IC50=<0.03µM). Compound 10 was further evaluated for antagonist and other cell-based activities, in vitro stability and pharmacokinetics.

The assessment of sagittal changes with twin block appliance in patients with decelerating growth phase.

INTRODUCTION: The main reason for seeking orthodontic treatment for Class II malocclusions is aesthetic improvement. Growth modification treatment procedures offer better results for a patient with significant potential growth. AIM: The aim of this cephalometric clinical study was to distinguish skeletal and dental corrections on skeletal class II division I growing subjects with Twin Block therapy (TB) and the changes were assessed using SO-analysis by Pancherz. MATERIALS AND METHODS: Strict diagnostic protocol viz. growing individuals with horizontal growth pattern, skeletal class II due to retrognathic mandible with positive VTO, bilateral class II molar relation, minimal crowding in either arch or overjet more than 5mm was used. Out of 28 selected cases,17 patients received TB therapy and 11 patients were maintained as control group. Standard removable TB appliances with lower incisor capping were delivered to treatment group. The horizontal advancement was about 8mm and 2-3mm vertical opening between the upper and lower central incisors were maintained for all the cases. The mean time interval between the initial (T1)and post treatment (T2) cephalograms of Twin-Block group was 11 month,with a range of 8 month to 13 month. In the control group, the mean time interval between the first (C1)and second (C2) cephalometric films was 12 month,with a range of 10 month to 14 month.T1and T2 cephalograms were traced and S-O analysis was used to segregate dental and skeletal effects. STATISTICAL ANALYSIS: SPSS software was used for statistical analysis. RESULTS: Skeletal Changes: In this study, the mean movement of maxilla was 0.67mm which represents significant restriction of forward maxillary growth in contrast to control groups. Dental Changes: In this study the maxillary molars appear to move distally with a mean value of 0.13mm. Comparing this to the movement of maxillary jaw base itself, maxillary distal movement of molar is less. But still it contributes to Class II correction. CONCLUSION: The overjet reduction and molar relation correction are more skeletal in nature.

Novel heterocyclic thiosemicarbazones derivatives as colorimetric and "turn on" fluorescent sensors for fluoride anion sensing employing hydrogen bonding.

Two novel heterocyclic thiosemicarbazone derivatives have been synthesized, and characterized, by means of spectroscopic and single crystal X-ray diffraction methods. Their chromophoric-fluorogenic response towards anions in competing solvent dimethyl sulfoxide (DMSO) was studied. The receptor shows selective recognition towards fluoride anion. The binding affinity of the receptors with fluoride anion was calculated using UV-visible and fluorescence spectroscopic techniques.

An efficient triazole-based fluorescent "turn-on" receptor for naked-eye recognition of F- and AcO-: UV-visible, fluorescence and 1H NMR studies.

An efficient colorimetric receptor was developed by a simple convenient method which exhibited naked-eye sensitivity for fluoride and acetate in a biologically competing solvent like DMSO. The receptor developed, portrayed a substantial change in the UV-visible absorption characteristics upon addition of fluoride and acetate anions over other anions. The binding constants showed that the binding ability of receptor towards F(-) anion was slightly higher than that of the AcO(-) anion. Job's plots indicated the formation of a (1:1) complex (receptor:anion) of receptor with fluoride and acetate anions respectively. A "turn on" fluorescence response with a red shift was observed upon fluorescence titration. (1)H NMR titration experiments revealed the mechanism to be driven by the hydrogen bonding interaction of amide NH and phenol OH of the receptor molecule which was followed by deprotonation in the receptor by the F(-) and AcO(-) anions.

1, 5-Bis (2-hydroxyacetophenone)thiocarbohydrazone: a novel colorimetric and fluorescent dual-mode chemosensor for the recognition of fluoride.

1,5-Bis (2-hydroxyacetophenone)thiocarbohydrazone (H4L) has been synthesized and characterized by means of spectroscopic and single crystal X-ray diffraction methods. Interactions of the H4L with a variety of anions were investigated using a combination of UV-visible and fluorescence spectroscopic methods in a biological competing solvent DMSO. The H4L has a high degree of selectivity for fluoride over other anions. (1)H NMR titration experiments indicate that a deprotonation process is involved in the chemo sensing process.

4-Salicylideneamino-3-methyl-1,2,4-triazole-5-thione as a sensor for aniline recognition.

Tridentate triazole based Schiff base 4-salicylideneamino-3-methyl-1,2,4-triazole-5-thione has been found to selectively detect toxic aromatic amines such as aniline and benzene-1,4-diamine by simple titration techniques like UV-visible, fluorescence spectral studies (PL) and 1H NMR titrations. The Schiff base receptor utilizes, thione sulfur, NH-thione and the phenolic hydroxyl group to form hydrogen bonded adduct of aniline and benzene-1,4-diamine with high binding affinity, followed by a slow removal of the corresponding hydrogens thus providing a promising candidate and an unique receptor for toxic aromatic amines.

A software framework for multimodal interactive simulations (SoFMIS).

The development of a multimodal interactive simulation is a very elaborate task due to the various complex software components involved, which run simultaneously at very high rates with maximum CPU load. In this work, we propose a multimodal parallel simulation framework called SoFMIS to create rapid interactive simulations such as surgical simulations. Our framework offers great flexibility and customization allowing simulation developers and researchers to concentrate on the simulation logic rather than component development.

Synthetic approach toward the total synthesis of kempane diterpenes via transannular Diels-Alder strategy.

Total syntheses of two new (+/-)-kempane derivatives 30 and 47 were achieved with transannular Diels-Alder reaction (TADA) serving as the key step for the stereoselective formation of tricyclic [6.6.5] system 3. This synthetic approach also reveals that the geometry of the C3 group of such a tricyclic system plays an important role for the formation of the seven-membered kempane skeleton.

Engaging zwitterions in carbon-carbon and carbon-nitrogen bond-forming reactions: A promising synthetic strategy.

An Account of carbon-carbon and carbon-nitrogen bond-forming reactions mediated by zwitterions generated by the addition of organic nucleophiles to activated unsaturated systems highlighting their synthetic potential is presented.

Synthetic studies toward highly functionalized 5beta-lanosterol derivatives: a versatile approach utilizing anionic cycloaddition.

Stereoselective synthesis of the potentially biologically valuable 5beta-lanosteroidal-type backbone was achieved via anionic cycloaddition. Synthesis of the two new bicyclic Nazarov intermediates 14 and 40 and their cycloaddition with chiral cyclohexenone 25 and further functional group manipulations resulted in highly functionalized tetracyclic intermediates 28 and 44. These synthetic intermediates could lead to the total synthesis of new lanosterol-based inhibitors.

Bis(mu-phenyl 2-pyridyl ketone N4,N4-butane-1,4-diylthiosemicarbazonato)bis[chlorocopper(II)].

The title compound, [Cu2(C17H17N4S)2Cl2], exhibits a dimeric structure related by a centre of symmetry. The monomers are linked to each other by the longest Cu-S apical distance observed to date among Cu(II) square-pyramidal complexes of N4-substituted thiosemicarbazones. Each Cu(II) atom deviates from the coordination square plane, which contains the pyridyl and imine N atoms, the thiolate S atom and the Cl- anion, towards the S atom of the adjacent monomer. The dimers pack in a zigzag manner through the crystal.

Strategies for heterocyclic construction via novel multicomponent reactions based on isocyanides and nucleophilic carbenes.

This Account focuses mainly on our recent endeavors in the area of multicomponent reactions (MCRs) involving zwitterionic species generated by the addition of isocyanides and nucleophilic carbenes such as dimethoxycarbene and N-heterocyclic carbenes to activated alkynes. The strategy employed encompasses the interception of 1:1 zwitterionic species, generated in situ with a wide range of electrophiles. The new MCRs developed offer an efficient and convenient entry into several heterocycles of biological and synthetic importance.

Spectral studies and structure of a 2-hydroxyacetophenone 3-hexamethyleneiminyl thiosemicarbazonate(-2) copper(II) complex containing 1,10-phenanthroline.

The spectral studies and structure of a ternary complex of copper(II) with 2-hydroxyacetophenone 3-hexamethyliminylthiosemicarbazonate (L(2-)) and 1,10-phenanthroline (phen) are reported. The thiosemicarbazone binds to the metal as a dianionic ONS-donor (L(2-)) ligand, and forms a complex of the stoichiometry [CuLphen]. The copper(II) complex was characterized by IR and UV/Vis spectroscopies, as well as by solid state room-temperature magnetic susceptibility. Spin Hamiltonian and bonding parameters of the compound are calculated from the EPR spectra. Computer simulation of EPR spectrum in DMF at 77 K aided the calculation of magnetic and bonding parameters of the compound. The structure of the compound is solved by single crystal X-ray diffraction. The geometry around copper is distorted square pyramidal.

Di-2-pyridyl ketone N4,N4-(butane-1,4-diyl)thiosemicarbazone.

The title compound, C(16)H(17)N(5)S, is in the thione form and crystallizes with two independent molecules in the asymmetric unit. In both molecules, the pentamethyleneimine five-membered ring adopts an envelope conformation, and in one of the molecules this ring shows positional disorder. The thione S and hydrazine N atoms are in the Z configuration with respect to the C-N bond.

A novel three-component reaction for the diastereoselective synthesis of 2H-pyrimido[2,1-a]isoquinolines via 1,4-dipolar cycloaddition.

[reaction: see text] The 1,4-dipole derived from isoquinoline and DMAD has been shown to react readily with N-tosylimines resulting in the diastereoselective synthesis of 2H-pyrimido[2,1-a]isoquinoline derivatives.

Bis[1-(pyridin-2-yl)ethanone-kappa N 4-phenylthiosemicarbazonato-kappa 2N4,S]manganese(II).

One half of the molecule of the title complex, [Mn(C(14)H(13)N(4)S)(2)], is related to the other half by a twofold axis passing through the Mn atom. This high-spin Mn atom is six-coordinated, in an octahedral geometry, by the azomethine N, the pyridyl N and the thiolate S atom of two planar 1-(pyridin-2-yl)ethanone N(4)-phenylthiosemicarbazone ligands. In the crystal, the molecules are interconnected by N-H.S and C-H.N interactions, forming a three-dimensional network.

Novel pyridine-catalyzed reaction of dimethyl acetylenedicarboxylate with aldehydes: formal [2 + 2] cycloaddition leading to 2-oxo-3-benzylidinesuccinates.

[reaction: see text]. The 1,4-zwitterionic intermediate generated from pyridine and DMAD adds to aldehydes in a formal [2 + 2] manner, resulting in the facile synthesis of 2-oxo-3-benzylidinesuccinates.